8-aza tetracycline compounds   

Abstract: The present invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The variables for Structural Formula I are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula I and its therapeutic use.

This application claims the benefit of U.S. Provisional Application No. 61/215,747, filed on May 8, 2009. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The tetracyclines are broad spectrum anti-microbial agents that are widely used in human and veterinary medicine. The total production of tetracyclines by fermentation or semi-synthesis is measured in the thousands of metric tons per year.

The widespread use of tetracyclines for therapeutic purposes has led to the emergence of resistance to these antibiotics, even among highly susceptible bacterial species. Therefore, there is need for new tetracycline analogs with improved antibacterial activities and efficacies against other tetracycline responsive diseases or disorders.

SUMMARY

Compounds of Formula I are new tetracycline analogs with improved antibacterial activities and efficacies against other tetracycline responsive diseases or disorders:

Pharmaceutically acceptable salts of the compound of Formula I are also included. A first embodiment of the invention includes values for the variables in Formula I are provided below:

X is selected from hydrogen, C1-C6 alkyl, phenyl, and C1-C6 alkoxy, wherein each C1-C6 alkyl and C1-C6 alkoxy represented by X is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy or halo(C1-C6)alkoxy;

Y is selected from hydrogen, fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6) alkylene-N(R1)(R2) and phenyl, wherein each of R1 and R2 is independently selected from hydrogen, and C1-C6 alkyl;

Z is selected from hydrogen, halo, C1-C6 alkyl, phenyl, —N(R3)(R4), (C1-C6) alkylene-N(R5)(R6), wherein R3 is selected from hydrogen, C1-C6 alkyl, (C1-C6) alkylene-phenyl, phenyl, (C1-C6) alkylene-(C3-C7 cycloalkyl), (C1-C6) alkylene-O—(C1-C6 alkyl), (C1-C6) alkylene-N(R5)(R6), —C(O)—(C0-C6) alkylene-N(R5)(R6), and —C(O)—(C1-C6 alkyl); R4 is selected from hydrogen, C1-C6 alkyl; or R3 and R4 are taken together with the nitrogen atom to which they are bound to form a (4-7 membered) heterocyclic ring optionally containing one additional heteroatom selected from S, O or N; R5 is selected from hydrogen, C1-C6 alkyl and phenyl; R6 is selected from hydrogen and C1-C6 alkyl; or R5 and R6 are taken together with the nitrogen atom to which they are bound to form a (4-7 membered) heterocyclic ring optionally containing one additional heteroatom selected from S, O or N, wherein each (C1-C6) alkyl, (C1-C6) alkylene or a (4-7 membered) heterocyclic ring in the group represented by Z is optionally substituted with fluoro, —OH, or —CH3; and

wherein each phenyl in the group represented by X, Y, Z, R3 and R5 is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6) alkyl, unsubstituted C1-C6 alkoxy, halo(C1-C6)alkoxy, cyano or nitro.

In certain aspects of the first embodiment, R3 is additionally selected from —C(O)H, —C(O)-phenyl, and —S(O)2—R5.

In a specific aspect of the first embodiment, Y and Z are not simultaneously hydrogen.

Another embodiment of the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound disclosed herein or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is used in therapy, such as treating an infection in a subject.

Another embodiment of the present invention is a method of treating an infection in a subject comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an infection in a subject.

Another embodiment of the present invention is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for therapy, such as treating an infection in a subject.

DETAILED DESCRIPTION

The present invention is directed to a compound represented by Structural Formula I or a pharmaceutically acceptable salt thereof. Values and alternative values for the variables in Structural Formula I are defined as the following:

X is hydrogen, C1-C6 alkyl, phenyl or C1-C6 alkoxy. Each C1-C6 alkyl or C1-C6 alkoxy in the group represented by X is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy or halo(C1-C6)alkoxy. X is hydrogen or C1-C6 alkyl. Alternatively, X is hydrogen.

Y is hydrogen, fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6) alkylene-N(R1)(R2) or phenyl. Alternatively, Y is fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6) alkylene-N(R1)(R2) or phenyl. Each C1-C6 alkyl, —(C0-C6) alkylene or C1-C6 alkoxy in the group represented by Y is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy or halo(C1-C6)alkoxy. Y hydrogen, chloro, fluoro, —N(CH3)(CH3), —OCH3, phenyl or (C1-C6)alkyl.

Z is hydrogen, halo, C1-C6 alkyl, phenyl, —N(R3)(R4) or (C1-C6) alkylene-N(R5)(R6). Alternatively, Z is hydrogen, C1-C6 alkyl, phenyl or N(R3)(R4). Alternatively, Z is hydrogen, —NH2, —NH(CH2)2CH3, —NH(CH2)2OCH3, —NHCH2CF3 or —NHCH2C(CH3)2CH2N(CH3)CH3. In another alternative, Z is hydrogen.

Each R1 and R2 is independently hydrogen or C1-C6 alkyl.

R3 is hydrogen, C1-C6 alkyl, —(C1-C6 alkylene)-phenyl, phenyl, —(C1-C6 alkylene)-(C3-C7 cycloalkyl), —(C1-C6 alkylene)-O—(C1-C6 alkyl), —(C1-C6 alkylene)-N(R5)(R6), —C(O)—(C0-C6 alkylene)-N(R5)(R6) or —C(O)—(C1-C6 alkyl). Alternatively, R3 is additionally selected from —C(O)H, —C(O)-phenyl, and —S(O)2—R5.

R4 is hydrogen or C1-C6 alkyl.

Alternatively, R3 and R4 are taken together with the nitrogen atom to which they are bound to form a (4-7 membered) heterocyclic ring optionally containing one additional heteroatom selected from S, O or N.

R5 is hydrogen, C1-C6 alkyl or phenyl.

R6 is selected from hydrogen and C1-C6 alkyl; or

Alternatively, R5 and R6 are taken together with the nitrogen atom to which they are bound to form a (4-7 membered) heterocyclic ring optionally containing one additional heteroatom selected from S, O or N.

Each (C1-C6) alkyl, (C1-C6) alkylene or a (4-7 membered) heterocyclic ring in the group represented by Z is optionally substituted with fluoro, —OH, or —CH3.

Each phenyl in the group represented by X, Y, Z, R3 and R5 is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy, halo(C1-C6)alkoxy, cyano or nitro. Preferably, each phenyl in the group represented by X, Y, Z, R3 and R5 is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy or halo(C1-C6)alkoxy. More preferably, each phenyl in the group represented by X, Y, Z, R3 and R5 is optionally substituted with fluoro, —CF3, —OCH3 or —OCF3.

A second embodiment is a compound of Structural Formula II, or a pharmaceutically acceptable salt thereof:

Values and alternative values for the variables in Structural Formula II are as defined for Structural Formula I above. Alternatively, for Structural Formulas I or II, Y is hydrogen, chloro, fluoro, —N(CH3)(CH3), —OCH3, (C1-C6) alkyl, or phenyl optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy, halo(C1-C6)alkoxy, cyano or nitro and Z is selected from hydrogen, C1-C6 alkyl, phenyl and N(R3)(R4), wherein the phenyl in the group represented by Z is optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy, halo(C1-C6)alkoxy, cyano or nitro. In another alternative, Y is hydrogen, chloro, fluoro, —N(CH3)(CH3)—OCH3, (C1-C6) alkyl, or phenyl optionally substituted with halo, unsubstituted C1-C6 alkyl, halo(C1-C6)alkyl, unsubstituted C1-C6 alkoxy, halo(C1-C6)alkoxy, cyano or nitro, and Z is hydrogen, —NH2, —NH(CH2)2CH3, —NH(CH2)2OCH3, —NHCH2CF3 or —NHCH2C(CH3)2CH2N(CH3)CH3. In yet another alternative, Z is hydrogen, —NH2, —NH(CH2)2CH3, —NH(CH2)2OCH3, —NHCH2CF3 or —NHCH2C(CH3)2CH2N(CH3)CH3 and Y is hydrogen, chloro, fluoro, or —N(CH3)(CH3).

In a specific aspect of the second embodiment, Y and Z are not simultaneously hydrogen.

A third embodiment is a compound of Structural Formula III, or a pharmaceutically acceptable salt thereof:

Values and alternative values for the variables in Structural Formula III are as defined for Structural Formula I above. Alternatively, Y is hydrogen, chloro, fluoro, —N(CH3)(CH3), —OCH3, phenyl or (C1-C6)alkyl and X is hydrogen or (C1-C6)alkyl. In one specific aspect of the third embodiment, Y is not hydrogen. In another specific aspect of the third embodiment, Y is fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6) alkylene-N(R1)(R2) and phenyl.

Specific examples of compounds of the invention are represented by Structural Formula I, wherein X, Y and Z are as defined in the table below:

Compound # X Y Z 100 101 102 103 104 105 106 107 108

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